1. Field of the Invention
Lactulose, or 4-O-.beta.-D-galactopyranosyl-D-fructose, is a synthetic disaccharide which is synthesized by the isomerization of lactose, or 4-O-.beta.-D-galactopyranosyl-D-glucose, a widely available natural disaccharide. Current processes, however, result in low yields which are difficult and expensive to purify. Thus, the high cost of production and difficulty of preparation have provided an incentive to develop an effective and efficient preparation method. This invention relates to a continuous process for isomerizing lactose to lactulose with boric acid as a complexing agent which provides a high-quality product at a cost substantially lower than that currently available.
2. Description of the Relevant Art
Lactulose was first prepared by a Lobry deBruyn-Alberda van Ekenstein alkaline isomerization of lactose in dilute calcium hydroxide solution (Montgomery and Hudson. 1930. J. Am. Chem. Soc. vol. 52, pp. 2102-2106). Other strong alkalis such as sodium hydroxide and potassium hydroxide and strong organic bases have also been utilized in the isomerization reaction. These methods resulted in low yields, however, due to numerous side reactions which lead to the formation of degradation by-products difficult to separate from the reaction mixture. The by-products also imparted a brownish color to the lactulose syrup, and purification steps were necessary not only for their removal but also for that of unreacted starting materials and calcium ions as well.
Subsequent methods for producing lactulose utilized complexing reagents to shift the pseudo-equilibrium established during base-catalyzed isomerization in favor of the ketose and to prevent degradative side reactions. The use of aluminate (U.S. Pat. No. 3,546,206 issued Dec. 8, 1970) and borate ions (Mendicino, J. F. 1960. J. Am. Chem. Soc., vol. 82, pp. 4975-4070; Carubell, R. 1966. Carbohydr. Res. vol. 2 pp. 480-485) have been reported for this purpose with varying degrees of effectiveness. The lactulose yield is higher and the product more pure (U.S. Pat. No. 3,546,206, supra; Mendicino, supra), however, both reagents are very difficult to remove from the reaction mixture. In addition a borate:sugar ration of 50:1 (as reported by Mendicino, supra) is required for optimal yield of product, thereby substantially increasing the difficulty of removing borate from the reaction mixture after isomerization is complete.
Base-catalyzed isomerizations have also been carried out utilizing amines as catalysts. Ammonia (Hough et al. 1953. J. Chem. Soc. pp. 2005-2009) has been successfully employed for converting lactose to lactulose; however, both primary and secondary amines have resulted in the formation of by-products such as glycosylamines (Ellis and Honeyman. 1955. Adv. Carbohydr. Chem. vol. 10, pp. 95-168) and Amadori (Hodge, J. E. 1955. Adv. Carbohydr. Chem. vol. 10, pp. 169-205) compounds. The use of the teritary amine triethylamine avoided this problem (U.S. Pat. No. 3,514,327 issued May 26, 1970) since the amine did not form adducts with reducing sugars; however, there was considerable alkaline degradation associated with the process. The combination of the treatment of lactose in the presence of borate (at a molar ratio of 1:1) with tertiary amine (Hicks and Parrish. 1980. Carbohydr. Res. vol. 82, pp. 393-397; Hicks, U.S. Pat. No. 4,273,922 issued Jun. 16, 1981) minimized degradative side-reactions and resulted in high yields of lactulose with a minimal use of borate.
Carobbi et al. (U.S. Pat. No. 4,536,221 issued Aug. 20, 1985) disclosed the isomerization of lactose to lactulose in the presence of a basic magnesium salt and sodium hydrosulphite. Extensive purification is required, however, in order to remove unreacted lactose, Mg and Na ions and the related anions. The addition of hydrosulphite results in a reduction in the amount of degradation products in the reaction mixture. Sulphite, bisulphite and phosphite ions are believed to react with these products to form sugar sulphonic acids and sugar phosphonic acids. These compounds pose disposal problems because they are environmentally undesirable however, therefore they must subsequently be removed. Alternatively, de Haar et al. (U.S. Pat. No. 5,026,430 issued Jun. 25, 1991) taught the addition of hydrogen peroxide or sodium chlorite to reaction mixtures containing sulphite, bisulphite or phosphite. Hydrogen peroxide serves to oxidize the degradation products of lactulose to carboxylic acids which can be removed by ion exchangers. Sodium chlorite is also an effective coreagent, however, due to the requirement for sodium hydroxide in the isomerization reaction, corrosive compounds such as chlorine and chlorodioxide are formed.
While the conversion of lactose to lactulose in the presence of borate has proven to be particularly effective, a commercially feasible process has remained elusive due to the difficulty of effectively separating the lactulose product from the reaction mixture.